Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Obenauf, AC; Zou, Y; Ji, AL; Vanharanta, S; Shu, W; Shi, H; Kong, X; Bosenberg, MC; Wiesner, T; Rosen, N; Lo, RS; Massagué, J.
Therapy-induced tumour secretomes promote resistance and tumour progression.
Nature. 2015; 520(7547): 368-372.
Doi: 10.1038/nature14336
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- Leading authors Med Uni Graz
- Obenauf Anna Christina
- Co-authors Med Uni Graz
- Wiesner Thomas
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- Abstract:
- Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression. The tumour-promoting secretome of melanoma cells treated with the kinase inhibitor vemurafenib is driven by downregulation of the transcription factor FRA1. In situ transcriptome analysis of drug-resistant melanoma cells responding to the regressing tumour microenvironment revealed hyperactivation of several signalling pathways, most prominently the AKT pathway. Dual inhibition of RAF and the PI(3)K/AKT/mTOR intracellular signalling pathways blunted the outgrowth of the drug-resistant cell population in BRAF mutant human melanoma, suggesting this combination therapy as a strategy against tumour relapse. Thus, therapeutic inhibition of oncogenic drivers induces vast secretome changes in drug-sensitive cancer cells, paradoxically establishing a tumour microenvironment that supports the expansion of drug-resistant clones, but is susceptible to combination therapy.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenocarcinoma - drug therapy Adenocarcinoma - metabolism Adenocarcinoma - pathology Adenocarcinoma - secretion
- Animals -
- Cell Line, Tumor -
- Cell Movement - drug effects
- Cell Proliferation - drug effects
- Cell Survival - drug effects
- Clone Cells - drug effects Clone Cells - pathology
- Disease Progression -
- Down-Regulation - drug effects
- Drug Resistance, Neoplasm - drug effects
- Enzyme Activation - drug effects
- Female -
- Humans -
- Lung Neoplasms - drug therapy Lung Neoplasms - metabolism Lung Neoplasms - pathology Lung Neoplasms - secretion
- Melanoma - drug therapy Melanoma - metabolism Melanoma - pathology Melanoma - secretion
- Metabolome - drug effects
- Mice -
- Neoplasm Metastasis - drug therapy Neoplasm Metastasis - pathology
- Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use
- Proto-Oncogene Proteins B-raf - antagonists & inhibitors
- Proto-Oncogene Proteins c-akt - metabolism
- Proto-Oncogene Proteins c-fos - deficiency
- Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
- Receptor, Epidermal Growth Factor - antagonists & inhibitors
- Signal Transduction - drug effects
- Tumor Microenvironment - drug effects